Beta-Lactam Study notes Flashcards
What are the 5 ways antibiotics work
- inhibition of cell wall synthesis
- Inhibition of protein synthesis
- Inhibition of nucleic acid synthesis
- Alteration of cell membrane function
- Alteration of cell metabolism
What is the difference between Gram + and Gram - bacterial cell walls.
The cell walls of bacteria are very porous and allow water in and out, but also do not allow osmotic pressure to cause lysis. * The cell wall in gram +ve bacteria is much thicker but it is also very porous as mentioned above so most drugs can penetrate it easily. * In gram –ve bacteria there is an outer lipopolysaccharide barrier surrounding the cell wall which prevents water and polar molecules from coming in. o These bacteria allow water and components of life to enter via porins which are channels in this membrane (gram +ve have them as well). o In general, drugs have less chance of passing through if they are large (vancomycin), have a positive charge, or are hydrophobic. * Bacteria also produce β-lactamases, enzymes which break up the β-lactam ring. o In gram +ve organisms they are secreted outside the cell, in gram –ve they are secreted in the periplasmic space.
What are the three types of B-lactam antibiotics?
Penicillins, cephalosporins and carbapenems.
What is the MOA of Beta-lactam antibiotics
Bacteria have rigid cell walls that are not found in animal cells, that completely surrounds the cytoplasmic membrane. This maintains the shape of the cell and prevents cell lysis.
* The cell wall is composed of a cross linked polymer (peptidoglycan) consisting of polysaccharides and polypeptides.
* The polysaccharides contain alternating amino sugars. One of these sugars terminates in Dalanyl- D-alanine (D-Ala-D-Ala).
* Penicillin-binding proteins (PBPs) catalyze the transpeptidase reaction which removes the terminal alanine and cross links it with another amino sugar which gives the cell wall its integrity.
* β-Lactams are structural analogs of D-Ala-D-Ala and thus bind to PBPs at the active site. This prevents transpeptidation, peptidoglycan synthesis is blocked and the cell dies.
* In order for the β-Lactam to work effectively, the bacteria must have active growth and cell wall synthesis.
* β-lactams bind to different PBPs, as well as the size and charge of the molecules affects how they work.
What are the 4 primary mechanisms of resistance to the B-lactam antibiotics?
- The primary mechanisms of resistance to the be β-lactam antibiotics are:
* Bacterial β- lactamase (BL) production (MOST COMMON MOA)
i. Gram +ve –outside cell wall
ii. Gram –ve –in periplasmic space - Alteration in the PBP’s.
- Altered permeability so that the antibiotic cannot reach its target.
- The presence of an efflux pump.
Why is Penicillin the most common B-lactam to cause hypersensitivity reactions?
Penicillin is metabolized to benzylpenicilloyl, which is also known as the major determinant of penicillin allergy.
Other metabolites are formed and are known as minor determinants but account for a minority of allergic reactions. o This is why penicillin is the most common β-lactam to cause hypersensitivity.
What is the difference between Type 1, 2 and 3 allergic reactions with penicillin?
TYPE 1:
- IgE mediated
- Symptoms: urticaria, angioedema, wheezing, hypotension and anaphylaxis
- Most occur in first 72 hours, with the presence of itchiness suggesting a milder reaction
- If someone has a severe type 1 reaction, ALL penicillins should be avoided and other B-lactams on a risk vs. benefit basis.
Type2:
Type 2 reactions occur very rarely and usually present as hemolytic anemia. They are IgG and IgM related and occur > 72 hours later. They are drug specific and usually do not exhibit cross-reactivity.
Type 3: Type 3 reactions are delayed and present often as serum sickness, small vessel vasculitis, as well as many also very rare
Late >72 reactions are most commonly what?
The epidemiology of type 4 reactions are unknown but usually late (>72 hours) and often present as a dermatitis, maculopapular or mobilliform rash. Are T-cell related and in worst case scenarios can cause Steven-Johnson syndrome (SJS) or toxic epidermal necrolysis
Describe the types of reactions that are immediate <1 to 72 hours
Urticaria, Laryngeal edema, bronchospasm, hypotension, local swelling, angioedema
What are delayed reactions (>72 hrs)
Morbilliform rash, Maculopapular rash, serum sickness, urticaria, SJS, Interstitial nephritis, Pulmonary infiltration, vasculitis, hemolytic anemia, neutropenia, thrombocytopenia.
Describe the concern with cross-reactivity between B-lactam antibiotics
Penicillins and Cephalosporins * It was originally thought that hypersensitivity occurred secondary to the β-lactam ring. It is now believed that cross-reactivity is more likely due to similarities within the side chain.
o Probably occurs less than 5% of the time.
o Amoxicillin shares a similar side chain to ampicillin, cefaclor, cefadroxil and cephalexin. o Cefazolin has a side chain that is not similar to any penicillin, and ceftazidime has been shown to not be cross-reactive with pen-allergic patients.
o Basically you have to address the likelihood of cross reacting due to side chain and severity. If the side chain is not similar, it is probably not going to cross-react. If it is a severe reaction risk vs benefit needs to be assessed.
What agents does penicillin share a similar side chain with?
Penicillin, cephalithin, cephalodrine, and cefoxitin
What is the likelihood of cross reactivity between penicillins and carbapenems?
1%
What should be investigated when looking into a patient’s allergy?
“Thorough investigation of patient allergies, including, but not limited to the specific drug that the patient received, the reaction experienced, temporal relationship of the reaction with regard to when the drug was administered, and concomitant drugs that the patient received during treatment with the alleged allergen.” (Terico and Gallagher, 2014)
Risk vs benefit always has to be addressed
Aside from allergic reactions, what other side effects can occur with b-lactams?
Hematologic
* Agranulocytosis, hemolytic anemia, problems with platelets.
Hepato-Biliary
* Can cause mild elevations of liver enzymes. * Ceftriaxone in particular is excreted in the bile and can bind to calcium causing biliary sludging.
Renal
* Nephrotoxicity rarely occurs with beta-lactams and is more of a problem with imipenem/cilastatin,(the cilastatin part) in high doses over prolonged periods.
Neurologic
* Lowered seizure threshold (at very high doses), more of a concern in patients with renal failure.
GI
* Many can cause non C. Diff diarrhea (ampicillin, and piperacillin among others).
* Third generation cephalosporins are probably more associated with C. Diff diarrhea
What does ceftriaxone potentially cause liver issues?
Ceftriaxone in particular is excreted in the bile and can bind to calcium causing biliary sludging.
What is the structure of Pencillins?
All penicillins contain a thiazolidine ring attached to a β-lactam ring that carries a secondary amino group. * The attachment of different sub-groups to the amino group determines the essential activity of the molecule. * If the β-lactam ring is cleaved, antibacterial activity is lost.
List the natural penicillins
Pen G
Pen G Benzathine
Pen V
Why is Pen V oral, and Pen G not?
Pen G is rapidly inactivated at low pH; administered parenterally.
o Due to β-lactam ring being broken down as a result of exposure to acid in stomach
- Pen V resists acid damage in the stomach and is administered orally (F = 60%).
o Has an electro-negative oxygen on the acyl side chain which produces and electron withdrawing effect which therefore protects it in an acidic environment. Pen G does not have this and this is why it is not PO
How does food affect penicillin absorption?
Food reduces and delays absorption of Pen V. Administer 1 hr before or 2 hrs after eating
How is penicillin eliminated?
Renally
What does probenecid do with regard to penicillin?
Probenecid slows renal elimination and can be used to sustain higher serum levels.
Describe the absorption of benzathin penicillin and when it is considered the drug of choice?
Benzathine penicillin, is slowly absorbed into the circulation, after intramuscular injection, and hydrolyzed to penicillin in vivo.
o It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose. o Used in syphilis
Describe the spectrum of activity of NATURAL penicillins
Gram + ve
- Effective against Streptococcus pyogenes (group A Strep), Streptococcus agalactiae (group B Strep) and varying against Streptococcus viridians group (alpha hemolytic strep).
- Effective against but there is increasing resistance among Streptococcus pneumoniae worldwide.
- Pen G covers Enterococcus faecalis but not faecium very well.
- Pen G will cover Listeria monocytogenes.
- Both cover C. diptheriae
PEN G covers neisseria meningitides
- Penicillin is effective against oral anaerobes (Actinomyces) and other anaerobes (peptostreptococcus).
- May also be used for Clostridium perfringens, clostridium tetani, syphilis
What is the Penicilinase-resistant penicillin?
CLOXACILLIN
Describe the structure of penicillinase-resistant penicillin?
These molecules have a isoxazolyl ring in the penicillin side chain which acts as electron withdrawing (acid stability) but also has a steric shield which prevents beta-lactamases from destroying the ring.
o A steric shield is a bulky molecule that protects a reactive molecule (beta-lactam ring) from reacting with something (beta-lactamase)
- Available orally and parenterally; oral administration should be on empty stomach as absorption is only about 35%.
- Significant liver metabolism; no dosage adjustment necessary in renal impairment (unless patient is anuric).
What is the spectrum of activity of penicillinase-resistant penicillin (Cloxacillin)?
Gram + ve * Similar to Penicillin, plus active against methicillin-sensitive Staph. Aureus (MSSA)
- Not effective against Enterococcus species, gram -ve bacteria and anaerobic bacteria
What are the three aminopenicillins
- Amoxicillin
- Amox/clav
- Ampicillin
Describe the structural chemistry of cephalosporins?
Still BETA-lactams but differ in that the ring is a 6 membered ring not 5 (like in penicillins).
* Variations among the cephalosporins are made at the R1 position (alters spectrum of activity) or at the R2 position (alters pharmacokinetics).
